Deaths and Cardiovascular Events in Men Receiving Testosterone T. Hugh Jones, BSc, MD, FRCP1; Kevin S. Channer, MD, FRCP2

JAMA. 2014;311(9):962-963. doi:10.1001/jama.2014.398.

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To the Editor We are concerned that the study by Dr Vigen and colleagues 1 has serious flaws in both design and interpretation.

First, Vigen et al 1 characterized testosterone treatment as filling a single prescription for any testosterone product and “once initiated, a patient was assumed to have continued treatment ….” This is insufficient for a definition of long-term testosterone therapy, especially when 17.6% received only 1 prescription. Moreover, there were no data on whether patients continued to regularly receive treatment.

Second, the mean testosterone level achieved after receiving testosterone therapy was only 332.2 ng/dL, which is just within the lower end of the normal range and indicates that many men were undertreated. The guidelines from the Endocrine Society recommend that the treatment level should be in the mid-normal range. In addition, testosterone dose may require titration.

Third, 63.3% of patients used a patch as the form of testosterone therapy at a dose of 2.5 mg/d. The usual dose in patch form to achieve an adequate testosterone level is 5 mg/d. 2 Furthermore, patches commonly cause skin reactions and, in our experience, many patients discontinue therapy because of this.

Despite these flaws, Vigen et al 1 reported almost half the mortality (5%), stroke (2.7%), and myocardial infarction (1.8%) rates in the testosterone-treated group compared with the untreated group (9% for mortality, 6.5% for stroke, and 5.6% for myocardial infarction). It is hard to understand how these absolute differences can be transformed to show a disadvantage of testosterone therapy. In addition, Vigen et al 1 used a complicated statistical approach that included a large number of variables to adjust the data.

When testosterone therapy has been used appropriately (eg, with licensed initiation doses that are then adjusted appropriately to achieve levels within the normal range), long-term studies have not identified any adverse cardiovascular effects. 3 Moreover, there are convincing data that overall mortality is lower in treated patients with hypogonadism. 4 5 Just as with thyroid therapy, both overtreatment and undertreatment may affect the clinical outcomes of patients.

Article Information Corresponding Author: T. Hugh Jones, BSc, MD, FRCP, Robert Hague Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust, Gawber Road, Barnsley S75 2EP, England (

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jones reported being an advisory board member for Bayer Healthcare, Lilly, Merck, and Novartis; being a consultant to Clarus Pharmaceuticals; receiving a grant from Bayer Healthcare United Kingdom; receiving payment for lectures from Bayer Healthcare, Lilly, and ProStrakan; and receiving travel expenses from Bayer Healthcare United Kingdom. Dr Channer reported receiving lecture fees from Bayer Healthcare.

Section Editor: Jody W. Zylke, MD, Senior Editor.

References 1 ↵ Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.


2 ↵ Arver S, Dobs AS, Meikle AW, et al. Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men. Clin Endocrinol (Oxf). 1997;47(6):727-737.


3 ↵ Carson CC III, Rosano G. Exogenous testosterone, cardiovascular events, and cardiovascular risk factors in elderly men: a review of trial data. J Sex Med. 2012;9(1):54-67.


4 ↵ Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97(6):2050-2058.


5 ↵ Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169(6):725-733.


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